Obesity results from a chronic energy imbalance in which energy expenditure is less than energy intake. Brown adipose tissue (BAT) is an important regulator of energy expenditure via its expression of mitochondrial uncoupling protein 1 (UCP1), and the ectopic expression of UCP1 in mice protects against the development of obesity and its related complications including insulin resistance and diabetes. In contrast, the deletion of UCP1 in mice results in greater obesity when mice are housed at thermoneutrality (30° C.), but not at 22° C., which is a stressful environment to these thermogenically impaired mice. Importantly, positron emission tomography (PET) imaging has indicated that BAT is less active in humans with both aging and obesity. However, the mechanisms mediating reductions in BAT activity are not currently understood.
Serotonin, also known as 5-hydroxytryptamine (5-HT), is a biogenic amine that has been studied extensively for its role in regulating behavior, appetite and energy expenditure via the central nervous system; functions that are largely conserved across all phyla that have a nervous system. Despite the extensive understanding of serotonin in the brain, the vast majority of serotonin (˜95%) in the body is found in the periphery where it is produced by the enzyme, tryptophan hydroxylase 1 (Tph1) which catalyzes the rate-limiting step in the synthesis of 5-HT from dietary tryptophan. Tph1 is genetically distinct from Tph2 which predominates in the brain stem and enteric neurons.
Mice deficient in Tph1 (Tph1−/−) have been generated that exhibit very low levels of circulating serotonin but maintain normal levels of serotonin in the brain due to the sustained presence of Tph2 which controls central serotonin production. Tph1−/− mice are viable and show no behavioral differences from wild-type animals and have normal body mass and insulin sensitivity when fed a chow diet. Since serotonin does not cross the blood brain barrier, Tph1−/− mice have been a valuable aid in unraveling the importance of peripheral serotonin in regulating gastro-intestinal and liver inflammation, insulin secretion and bone formation.
In addition to the ancient role of serotonin in regulating energy balance in both vertebrates and invertebrates, polymorphisms in Tph1 and serotonin receptor (HTR2A) genes have recently been associated with obesity and gestational diabetes. Further, high-fat diet-induced obesity has been found to result in increased levels of circulating serotonin in mice. However, whether changes in peripheral serotonin are directly linked to obesity or to changes in energy expenditure is not currently known.
Thus, it would be desirable to determine the role of peripheral serotonin in obesity, and to develop methods of treating obesity.